SUMMARY Despite significant advances in the surgical and medical management of congenital heart disease, congenital cardiac anomalies remain a leading cause of death in the newborn period. Most severe forms of congenital heart disease require multiple, staged surgical interventions. A significant source of the heightened morbidity and mortality associated with these operations is the development of cardiac adhesions. Adhesions are fibrous bands of scar tissue that connect two areas of the body not normally connected and arise due to unavoidable surgical trauma. Adhesions are exacerbated by excessive inflammation in the post-operative period. Dissection of adhesions significantly complicate reoperation by increasing operative and anesthetic time and amplifying the risks of perioperative bleeding and iatrogenic injury to the heart and great vessels, which are all associated with worse outcomes and increased cost. Currently there are no FDA approved products that reduce the incidence of the complications associated with reoperation in congenital heart surgery. We recently discovered that the LYST protein underlies the development of dense adhesions after cardiothoracic surgery and hypothesize that rational inhibition of LYST will attenuate excessive inflammation following surgery, thereby preventing adhesions formation. A top priority for Lyst Therapeutics is to de-risk the use of anti-LYST therapy to inhibit the formation of adhesions after cardiac surgery. In this proposal, we will investigate the use of cell- targeting and local delivery of LystaMab (a monoclonal anti-LYST antibody) to optimize its safety and efficacy for preventing pericardial adhesions. The successful development of anti-LYST therapy to mitigate the development of cardiac adhesions would represent a novel form of rationally designed immunomodulation that could significantly improve outcomes in the pediatric congenital heart population. Development of safe and effective strategy to prevent the formation of cardiac adhesions would significantly benefit children born with congenital heart defects requiring multiple surgeries and would overcome a major barrier to progress in the field of congenital heart surgery.